SUMMARY Dysfunctional mitochondria and mitochondrial DNA (mtDNA) mutations are hypothesized to drive aging phenotypes, but the mechanisms by which these age-related defects act are poorly understood. This proposal focuses on the mechanisms linking mitochondrial dysfunction, including mtDNA mutations, to aging phenotypes through the pleiotropic stress response known as cellular senescence. The senescence response is a permanent arrest of cell proliferation, accompanied by phenotypic changes, including the development of a senescence-associated secretory phenotype (SASP). The SASP entails the secretion of a myriad of pro- inflammatory cytokines, angiogenic factors, growth factors and proteases. However, in the case of mitochondrial dysfunction, the secretory and mitotic arrest phenotypes can be partially uncoupled. Depending on the extracellular environment, mitochondrial dysfunction can either drive SASP-like secretion in the absence of mitotic arrest, or can drive a senescence arrest that is notably free of SASP inflammatory components. We propose to use cultured human and mouse cells, and mouse models to critically determine the role of cellular senescence phenotypes in mitochondrial dysfunction-induced aging. Our specific aims are designed to answer the following questions: How does loss of mitochondrial function drive cellular senescence phenotypes? Does the accumulation of mtDNA mutations drive cellular senescence phenotypes in a mouse model, and can the elimination of senescent cells prevent mtDNA-induced tissue dysfunction? Finally, is mitochondrial dysfunction an inducer of cellular senescence phenotypes during normal aging and does a mouse model of delayed aging accumulate fewer senescent cells with age? If successful, our proposed experiments will provide an important link between mitochondrial function and physiological manifestations of aging. In addition to generating important basic knowledge, the experiments will also provide a new targets (dysfunctional mitochondria and senescent cells) for the development of potential interventions into aging and age-related diseases.